Process of making uric-acid derivatives.



'in Letters Patent of the United States to FRITZ AOll, OF MANNHEIM, GERMANY PATENT OFFICE.

', ASSIGNOR TO C. F. BOEIIRINGER d5 SOEI-INE, OF VVALDHOF, GERMANY.

PROCESS OF MAKING U RIC-ACID DERIVATIVES.

SPECIFICATION forming part of Letters Patent No. 632,828, dated September 12, 1899.

Application filed November 13 18971 To all whom it may concern:

Be it known that I, FRITZ AOH, a citizen of the Empire of Germany, residing at Mannheim, in the Empire of Germany, have invented certain new and useful Improvements in the Art of Obtaining the Derivatives of Uric Acid; and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

This invention relates to the art of obtaining the derivatives of uric acid, and in particular the alkyl derivatives-that is to say, those derivatives in which the hydrogen atoms of the imido groups of the uric acid are replaced, one, several, or all, by alkyl radicals, thus forming mono, di, tri, or tetra alkyl uric acids.

In order to clearly elucidate the position occupied by this invention with respect to the prior state of the art, I deem it bestto briefly review the same, so far as necessary, for pur poses of comparison.

Alkylized uric acids have formerly been prepared by the action of haloid ethers upon alkaline solutions of uric acid or of its alkyl derivatives. These processes are set forth Emil Fischer, granted December 27, 1898, No. 610,700, for Alkyl derivatives of uric acid (nun-co emu-co Serial No. 658,453. (Specimens) and process of making the same. The course of this alkylization is best represented with the aid of the structural formula of uric acids, the four imido groups or hydrogen atoms being each designated with a numeral, accord- 5 ing to the suggestion of Emil Fischer, (Bem'chte derDeutschen Ohemischen Gesellschufl, 17, p. 1786,) thus:

,uric-acid molecule under the former method takes place successively and in the order 1-4- 3-2, these numerals here and throughout this specification representing the particular hydrogen atoms designated by these numerals in the above formula.

In the examples given in the former methods l-monomethyl-uric acid is first formed, then by continuing the reaction (1-4) dimethyl-uric acid, then (1-4-3) trimethyl-uric acids, and finally (1'42'3'2) tetramethyl-uric acid. This course of alkylization is represented in the following series:

CH,.N-CO ornN-oo oo 1 I HNONH I have found as the result of my experiments and investigations in this field that the course of alkylization may be changed and caused to take place in another direction than that set forth in the patent above referred to. I have thus discovered a manner of carrying out the generic invention set forth in said application in a manner which is specifically new.

Under my new process the alkyl radicals co oo co are introduced into the uric-acid molecule, so as to replace the hydrogen atoms 1, 2, and 3, or, in other words, to be bonded to the nitro gen atoms of the imido groups 1, 2, and 3 instead of to those of the imido groups 1, 3, and 4, as in the aforesaid application. When the alkylization consists, specifically, in methylating or introducing methyl radicals into the uric acid under this novel method, there is produced the hitherto-unknown 1-2-3 trimethyl-uric acid. The conversion which takes place may be represented thus:

IIN-CO CH .NOO

Uric acid.

The eitectof my new method is not confined to alkylizing uric acid proper, but follows also when the same is applied to alkylizing partially-alkylized uric acids, the latter when treated according to the said new method yielding final products which dilfer from those obtained when applying the former methods. Thus, 6. g., if delta-dimethyl-uric acid, which according to the researches of Emil Fischer (Berirhtc, 28, p. 2482) has the formula of a (1-3) dimethyl-uric acid, undergoes further methylation under the old methods, either by the action of methyl-iodid upon the corresponding lead salt (Bem'chte, 28, p. 2484) or (under the above-named application to Fischer) by acting upon an alkaline solution or mixture of the dimethyluric acid with a haloid ether and heating,we obtain alpha-trirnethyl-uric acid or (1-3-4)- trimethyl-uric acid, a compound already 1-2-3-trimethyl-uric acid.

orI,N co oI-I,N -co oo o-NcH, oo o Nor1, oo oo I-INONH HNC-NOH3. 40

When, however, my new method is applied in methylating (l-3)-dimethyl-uric acid, the resulting product, though a trimethyl-uric acid, is not the one obtained above, but (1-3-2)- trimethyl-uric acid: 5

crI,N oo cH,N-co

oc o N.orI,--- oo ONOH3 so I H \CO I IIN-CN.H cH,N-o-N.1-I.

known. This change is exhibited thus: in juxtaposition for purposes of comparison:

OH N,CO OH N-CO GH N- CO 00 (JNCH 0O C--NOH 0O C-NH (1-2-3)-trirnethyl uric acid, (hydroxy-caffein.)

. placed by alkyl radicals being herein designated as uric acid proper) in an alkaline bath or solution at a low temperature, preferably the freezing-point. The new method is, moreover, particularly characterized by the fact that in dissolving the free or partially-alkylized uric acid enough alkali is added at the beginning of the operation that all of the imido groups are maintained completely saturated throughout the entire operation.

(1-3- 4)-trimethyl uric acid or alphatrlm ethyl-uric acid. (Berichte, 17, p. 1782, and 28, p. 484.)

(1-2-4)-trimetl1yl-uric acid or beta.-

trimethyl-uric acid. (Berichte, 28, p. 2478.

Under the former methods of alkylizing with the aid of alkali the process was carried out at a raised temperature and the amount of alkali employed was no more than that required by the haloid ether employed. From the above it will be seen that my invention, broadly considered, consists in changing the course of alkylization by causing the same to proceed at a low temperature and also in adding so much alkali that all of the imido groups of the uric acid acted on are continually kept saturated. Finally the invention consists in such further features, steps, and methods, all as will be hereinafter set forth, and pointed out in the claims.

The following examples will serve to illustrate what I consider the best manner of carrying out my invention, the proportions given being all expressed in weight.

1. Preparation of 1-2-3-tm'methyl-urz'c acid or hydrowy-cafi ein from uric acidpr0pe12- Ten parts of uric acid are brought into solution in two hundred parts of water by means of twenty parts (corresponding to five mole cules) of caustic potash of eightyper-cent. strength. The solution is well cooled with icewater, and thirty parts, corresponding to three and one-half molecules, of methyl-iodid are added, and the whole is then shaken until the methyl-iodid disappears. Of the three and one-half molecules of methyl-iodid only three molecules are necessary to furnish the necessary amount of methyl. The remaining one-half molecule of the iodid is added only for practical reasons and to assist the operation of the process. The quantity of the caustic potash added must be in the proportion of at least four molecules of the caustic potash to one molecule of the acid, the amount of five molecules of caustic potash to one of the acid given above being deemed preferable. It is desirable to then cool for the first twelve hours with ice-water. After the reaction is completed the clear alkaline solution is acidulated slightly and evaporated down or concentrated to one-half its volume. Anydimethyl-uric acid that may remain over will be separated out on standing for several hours while the solution is being cooled and is removed by filtration. The filtrate is thereupon evaporated or concentrated to one-half its volume until crystallization takes place. Upon cooling a large proportion of the resultant hydroXy-caifein crystallizes out in the form of fine needles. The remainder of the hydroXy-cafiein is obtained by first evaporating the filtrate to dryness and then extracting the hydroxy-caffein therefrom with a suitable solventsuch as, for example, chloroform. After the solvent has evaporated off the hydroxy-caffein remains as a slightly-colored crystalline mass, which is obtained in a perfectly pure condition by once dissolving the same in water.

The l-2-3-trimethyl-uric acid possesses all of the characteristic properties which have been ascertained by Em'il Fischer (see Lie- Zn'gs Annalen, 215, p. 268) for hydroXy-caffein prepared from caffein.

93. Preparation of Jf?-5-trimehyZ-uric acid 07' hyd'roccy-cafi ein from L -di methybm'z'c acid.5.8 parts of 1-3-dimethyl-uric acid are dissolved in fifty parts of water by 4.5 parts, corresponding to two molecules of caustic potash of eighty-per-cent. strength. The solution is cooled with ice-water and after adding 5.5 parts, corresponding to one and one-third molecules, of methyl-iodid the whole is shaken until the methyl-iodid disappears. The clear liquid is slightly acidulated and evaporated down to one-half its bulk. On cooling the hydroxy-caffein crystallizes out in colorless needles, which on redissolving in water and recrysiallizing may be obtained in a pure condition. This product is identical with the compound which has formerly been prepared from caffein.

In carrying out my invention, of which the above exam pl es are an illustration ,the methyliodid may be replaced by other haloid ethers,

such as methylchlorid or methyl-bromid. The esters of other acids besides the halogen acids may be employed for alkylizing under m yinvention. Thus, for example, the alkylesters of sulfuric acid, nitric acid, benzenesulfo-acid, &c., may be substituted for the methyl-iodid in the above two examples of carrying out my invention. Where other alkyl groups are introduced into uric acid, the corresponding halogen-alkyls or haloid ethers, such as ethyl-chlorid or iodid, are manifestly to be employed. Other alkalies may be used instead of the caustic potash, and instead of the aqueous alkaline solution alcoholic aqueous alkaline solution of the uric acid may be employed.

In general my process may be modified in many particulars without departing from my invention, which relates to the preparation of any alkyl-uric acids, as already stated, and consists, broadly, in changing the course of replacing the hydrogen atoms in uric acids by anyalkyl radicals and in causing the alkylization to proceed at a low temperature and also in adding enough alkali to keep all of the imido groups of the uric acid saturated.

As already stated, the term uric acid as employed in the claims generically comprises both uric acid proper-that is, the uric acid in which none of the imido groups have been alkylized-and mono-alkyl-uric acids, dialkyl-uric acids, &c.z'. 6., those uric acids in which one or more of the imido groups have been alkylized.

hat I claim, and desire to secure by Letters Patent of the United States, is

1. The process which consists in treating an alkaline solution of a uric acid with an alkylester at a low temperature.

2. The process which consists in dissolving a uric acid in Water by an alkali, the alkali being added in a proportion to keep all of the imido groups of the uric acid saturated, then lowering the temperature and adding an alkylester.

3. The process which consists in treating an alkaline solution of a uric acid with a haloid ether at a low temperature.

at. The process which consists in dissolving a uric acid in water by the aid of alkali, the alkali being added in a proportion suflicient to keep the imido groups of the uric acid saturated, then lowering the temperature and adding a haloid ether.

5. The process which consists in dissolving uric acid proper in water together with caustic potashin the proportion of at least four molecules of the caustic potash to one mole cule of the acid, then cooling the solution and then adding methyl-iodid in the proportion of three molecules to one molecule of the acid, and shaking the mixture.

6. The process which consists in dissolving the uric acid proper in water together with caustic potash in the proportion of at least 4 four molecules of the caustic potash to one tic potash, in the proportion of at least four molecules of the caustic potash to one molemolecule of the acid, then cooling the solution, and then adding methyl-iodid in the proportion of at least three molecules to one molecule of the acid, shaking the mixture and cooling fora long period.

'7. The process which consists in dissolving uric acid proper in water together with caustic potash in the proportion of at least four molecules of the caustic potash to one molecule of the acid, then cooling the solution and adding methyl-iodid in the proportion of at least three molecules to one molecule of the acid, shaking and cooling the mixture for a long period until the methyl-iodid disappears, and then acidulatiug and concentrating or evaporating the liquid, then filtering and concentrating or evaporating the filtrate and allowing a portion of the hydroxy-cafiein to separate out of the solution by crystallization.

8. The process which consists in dissolving uric acid proper in water, together with causcule of the acid, then cooling the solution, then adding methyl-iodid in the proportion of three and one-half molecules to one molecule of the acid, while continuously shaking the mixture cooling a second time for a long period, then acidulating and reducing the volume by evaporation or otherwise, then filtering and concentrating or evaporating the filtrate and allowing a portion of the hydroxycatfein to separate out of the solution by crystallization, again filtering and evaporating the filtrate to dryness and then extracting the remainder of the hydroxy-caifein from the residue with a' solvent of the same.

In testimony whereof I aifix my signature in presence of two witnesses.

FRITZ ACH.

Witnesses:

BERNHARD C. HESSE, JACOB ADRIAN. 

